USRE35593E - Azabicylo oxime compounds - Google Patents

Azabicylo oxime compounds Download PDF

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USRE35593E
USRE35593E US08/585,113 US58511396A USRE35593E US RE35593 E USRE35593 E US RE35593E US 58511396 A US58511396 A US 58511396A US RE35593 E USRE35593 E US RE35593E
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azabicyclo
hept
oct
compound
methoxycarboximidoyl
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Barry S. Orlek
Steven M. Bromidge
Steven Dabbs
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Beecham Group PLC
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Beecham Group PLC
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Priority claimed from GB898908365A external-priority patent/GB8908365D0/en
Priority claimed from GB898923299A external-priority patent/GB8923299D0/en
Priority claimed from US07/785,884 external-priority patent/US5278170A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • This invention relates to compounds having pharmaceutical activity, to a process for their preparation and their use as pharmaceuticals.
  • a novel group of compounds has now been discovered which also enhance acetylcholine function via an action at muscarinic receptors within the central nervous system and are therefore of potential use in the treatment and/or prophylaxis of dementia in mammals.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof ##STR3## wherein R 1 represents ##STR4## in which each of p and q independently represents an integer of 2 to 4, r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1;
  • R 2 is a group OR 4 , where R 4 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, a group OCOR 5 where R 5 is hydrogen or R 4 , or a group NHR 6 or NR 7 R 8 where R 6 , R 7 and R 8 are independently C 1-2 alkyl; and
  • halogen includes bromine, chlorine, fluorine and iodine, preferably fluorine.
  • Compounds of formula (I) are capable of existing in a number of stereoisomeric forms including geometric isomers such as syn and anti and, for certain compounds, enantiomers.
  • the invention extends to each of these stereoisomeric forms, and to mixtures thereof (including racemates).
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • pharmaceutically acceptable salt encompasses solvates and hydrates.
  • compounds of formula (I) or pharmaceutically acceptable salts thereof form solvates or hydrates, these also form an aspect of the invention.
  • p and q each independently represents 2 or 3. Most preferably p represents 2 and q represents 2 or 3.
  • Preferred combinations of (r,s,t) include (2,2,0), (2,1,1), (3,1,1), (2,1,0) and (3,1,0), most preferably (2,2,0).
  • R 4 and R 5 in R 2 are preferably selected from methyl, ethyl, allyl and propargyl.
  • R 6 , R 7 and R 8 are preferably methyl.
  • Suitable values for R 2 include methoxy, ethoxy, allyloxy, propargyloxy, acetoxy and dimethylamino, preferably methoxy.
  • R 3 examples include cyclopropyl, chloro, fluoro and bromo and when R 3 is a group (CH 2 ) n R 9 and n is O, suitable examples of R 9 include --CN, --OCH 3 or --C.tbd.CH, preferably CN. When n is 1, an example of R 9 is CN.
  • the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises:
  • R 2 ' represents R 2 or hydroxy
  • R 3 ' represents R 3 or a group convertible thereto, converting R 2 ' to R 2 when hydroxy, converting R 3 ' when other than R 3 to R 3 , wherein R 1 , R 2 and R 3 are as defined in formula (I), and thereafter optionally forming a pharmaceutically acceptable salt;
  • R 3 ' represents R 3 or a group convertible thereto, converting R 3 ' when other than R 3 to R 3 , wherein R 1 , R 2 and R 3 are as defined in formula (I), and thereafter optionally forming a pharmaceutically acceptable salt; or
  • reaction between the compounds of formulae (II) and (III) is preferably carried out in a hydroxylic solvent such as methanol or ethanol, at ambient temperature, or where appropriate, at elevated temperature.
  • a hydroxylic solvent such as methanol or ethanol
  • R 2 in compounds of formula (I) is a group OR 4 , NHR 6 or NR 7 R 8
  • a compound of formula (II) is conveniently reacted with a compound of formula (III) in which R 2 ' is R 2 .
  • R 2 in compounds of formula (I) is a group OCOR 5
  • a compound of formula (II) may be reacted with the compound of formula (III) in which R 2 ' is hydroxy, with subsequent acylation of the resulting oxime by treatment with a suitable acylating agent such as an acyl halide, for example acetyl chloride.
  • reaction between compounds of formulae (IV) and (V) may be carried out under standard conditions for the displacement of halogen by a nucleophile.
  • R 3 in compounds of formula (I) is fluoro
  • the residue M is suitably caesium, the caesium fluoride reagent being supported on calcium fluoride in dimethylformamide at elevated temperature for a prolonged period.
  • This route for introduction of R 3 fluoro is preferred where R 1 represents group (B).
  • R 3 in compounds of formula (I) is a group (CH 2 ) n R 9 and n is O
  • the residue M is suitably an alkali metal such as sodium or lithium.
  • R 9 is --CN or --OCH 3
  • the reaction is conveniently carried out at elevated temperature in an inert solvent such as dimethylsulphoxide or methanol.
  • R 3 in compounds of formula (I) is a group (CH 2 ) n R 9 and n is 1, the compound of formula (V) is suitably an organolithium or Grignard reagent.
  • the reaction may be carried out using conditions generally used for reactions with Grignard reagents, for example using anhydrous reagents under an inert atmosphere and at reduced temperature.
  • the product of the reaction of compounds of formulae (II) and (III) and formulae (IV) and (V) is a compound of formula (IIa): ##STR8## wherein R 2 ' represents R 2 or hydroxy and R 3 ' represents R 3 or a group convertible thereto, and R 1 , R 2 and R 3 are as defined in formula (I).
  • chlorinating agents include phosphorus pentachloride which undergoes reaction in nitromethane at reduced temperature, for example 0° C., and dichlorotriphenylphosphine (carbon tetrachloride/triphenyl phosphine) which undergoes reaction in acetonitrile at elevated temperature, for example at the boiling point of the solvent.
  • Suitable brominating agents include dibromotriphenylphosphine (carbon tetrabromide/triphenylphosphine) which undergoes reaction in acetonitrile at elevated temperature, for example at the boiling point of the solvent.
  • Suitable fluorinating agents include diethylaminosulphur trifluoride (DAST) which also undergoes reaction in acetonitrile at elevated temperature.
  • R 3 is ethnyl, it is preferably protected in the compound of formula (V) which is suitably lithium (trimethylsilyl) acetylene.
  • the trimethylsilyl protecting group is preferably removed after reaction of the compounds of formulae (II) and (III) by treatment with aqueous sodium hydroxide.
  • R 3 is cyclopropyl
  • a compound of formula (VI) in which L is preferably chloro or bromo may be treated with cyclopropyltrimethylsilane in the presence of aluminium trichloride in dichloromethane.
  • a compound of formula (VI) in which L is preferably C 1-4 alkoxy may be treated with a suitable organolithium or Grignard reagent, for example the reaction product of acetonitrile and lithium diisopropylamide. It will be appreciated that the resulting compound of formula (lI) will be in the form of the lithium enolate salt.
  • Novel compounds of formulae (II) and (Iva) also form part of the invention.
  • R 1 represents group (A)
  • R 1 represents group (A)
  • A represents a group convertible to COCl
  • B represents --(CH 2 ) j L 1 where L 1 is a leaving group or A and L 1 together represent --COO--; one of j, k and l is 1 and the other two independently represent an integer of 2 to 4.
  • R 10 represents hydrogen or an N-protecting group; to give a compound of formula (VIIa): ##STR11## in which X represents a group convertible to COCl or COBr, Z -- is an anion and the remaining variables are as previously defined;
  • A represents an electron withdrawing group
  • B represents hydrogen and R 10 represents --(CH 2 ) j L 2 where L 2 is a leaving group; one of k and l is 1 and the other and j independently represent an integer of 2 to 4; to give a compound of formula (VIIb): ##STR12## in which W represents an electron withdrawing group or X and the remaining variables are as previously defined;
  • Examples of the leaving groups L 1 and L 2 include halo such as bromo or chloro, tosyloxy and mesyloxy.
  • R 10 when an N-protecting group examples include benzyl and substituted benzyl.
  • B is (CH 2 ) j OTos or (CH 2 ) j OMes
  • a suitable reagent such as tosyl chloride or mesyl chloride
  • a base such as pyridine
  • the cyclisation may proceed at ambient temperature, or at elevated temperature in an inert solvent such as toluene.
  • a and L 1 together represent --COO--
  • the cyclisation may be carried out in a lower alkanol such as ethanol in the presence of acid such as hydrogen bromide.
  • X will be an alkoxycarbonyl group corresponding to the lower alkanol used for the cyclisation.
  • R 10 is an N-protecting group such as benzyl
  • this may be removed by conventional hydrogenation, preferably catalytically over a suitable catalyst such as Pd/C.
  • Examples of A when an electron withdrawing group include C 1-4 alkoxycarbonyl and cyano.
  • A is an electron withdrawing group such as C 1-4 alkoxycarbonyl
  • B is hydrogen and R 10 is --(CH 2 ) j L 2 where L 2 is, for example, chloro
  • the cyclisation may be effected by treatment of the compound of formula (VII) with lithium diisopropylamide.
  • the cyclisation may be carried out by pyrolysis, by the method of D. O. Spry and H. S. Aaron, J. Org. Chem., 1969, 34. 3674, to yield a compound where X is hydroxy.
  • the resulting ⁇ -keto ester is hydrolysed and decarboxylated under conventional conditions such as heating at reflux in dilute hydrochloric acid.
  • the carbonyl group may then be reduced to an X hydroxy group with a suitable reducing agent such as sodium borohydride in ethanol at ambient temperature, or sodium in ethanol at elevated temperature, such as the boiling point of the solvent, under an inert atmosphere sphere such as nitrogen, depending upon the stereo-chemistry required.
  • a suitable reducing agent such as sodium borohydride in ethanol at ambient temperature, or sodium in ethanol at elevated temperature, such as the boiling point of the solvent, under an inert atmosphere sphere such as nitrogen, depending upon the stereo-chemistry required.
  • the carbonyl group may be converted directly to an X cyano group with a suitable reagent such as tosylmethylisocyanide in an inert solvent such as dry dimethoxyethane, at depressed temperature, under basic conditions such as the presence of potassium t-butoxide.
  • a suitable reagent such as tosylmethylisocyanide in an inert solvent such as dry dimethoxyethane, at depressed temperature, under basic conditions such as the presence of potassium t-butoxide.
  • cyclisation is a Thorpe reaction which is catalysed by a base such as potassium t-butoxide at elevated temperature in a solvent such as toluene.
  • the resulting ⁇ -keto nitrile is hydrolysed and decarboxylated under conventional conditions such as heating at reflux in dilute hydrochloric acid.
  • Y 3 is --(CH 2 ) n L 4
  • the cyclisation may be carried out as described in EP-A No. 0094742 under basic conditions such as sodium hydride and potassium t-butoxide, in an inert polar solvent such as dimethyl formamide.
  • the conversion of K, W and X to COCl or COBr may be carried out conventionally.
  • An X hydroxy group may be converted to cyano by first converting it to a good laving group such as mesyloxy or tosyloxy and then displacing it with cyanide ion.
  • An X carboxy group may be obtained by conventional de-esterification of an X, K or W alkoxycarbonyl group.
  • R 10 is an N-protecting group and X, K or W is a benzyloxycarbonyl group
  • the de-esterification and deprotection steps may conveniently be effected simultaneously by conventional hydrogenation such as described above.
  • an X carboxy group may be obtained by conventional acid hydrolysis of an X, K or W cyano group.
  • a carboxy group may be treated with thionyl chloride at elevated temperature to give the chlorocarbonyl group, COCl or with thionyl bromide to give the bromocarbonyl group, COBr.
  • the compound of formula (VII) may be prepared by treating a compound of formula (IX): ##STR15## where R 11 is C 1-4 alkyl and the remaining variables are as previously defined, with lithium diisopropylamide, prepared in situ from diisopropylamine and n-butyllithium followed by reaction with a compound L 5 (CH 2 ) j L 1 where L 5 is a leaving group, in an inert solvent such as ether at depressed to elevated temperature. Both L 1 and L 5 are suitably bromo.
  • the compound of formula (VII) may be prepared by reacting the compound of formula (IX), treated with lithium diisopropylamide as before, with ethylene oxide in an inert solvent such as ether at depressed to elevated temperature.
  • the compound of formula (VII) where A and L 1 together represent --COO, j is 2, k is 2 and 1 is 1 may be prepared by a 1,3-dipolar cycloaddition reaction which involves reacting a compound of formula (X): ##STR16## with a compound of formula (XI): ##STR17## in which R 10 is an N-protecting group in the presence of a catalytic amount of trifluoroacetic acid.
  • A is an electron withdrawing group such as C 1-4 alkoxycarbonyl
  • B is hydrogen and R 10 is (CH 2 ) j L 2
  • the compound of formula (VII) may be prepared by reacting the compound of formula (IX) where R 10 is hydrogen with a compound L 5 (CH 2 ) j L 2 where L 5 is as previously defined, in a solvent such as acetone in the presence of a base such as potassium carbonate.
  • the leaving group L 5 is preferably bromo and L 2 is preferably chloro.
  • Compounds of formula (IX) are known compounds or may be prepared by analogous methods to those for preparing known compounds.
  • the compound of formula (IX) where k is 2, l is 1 and R 10 is benzyl may be prepared by the cyclisation of di-C 1-4 alkyl itaconate in the appropriate alkanol with benzylamine at elevated temperature, followed by reduction of the resulting oxo group at the 2-position of the pyrrolidine ring with BH 3 in tetrahydrofuran, at ambient to elevated temperature.
  • a compound of formula (X) may be obtained by the reaction of ⁇ -butyrolactone with ethyl formate in the presence of base such as sodium hydride followed by reaction of the resulting formyl derivative (as the enol salt) with formaldehyde.
  • a compound of formula (XI) may be obtained by the reaction of the primary amine R 10 NH 2 successively with chloromethyltrimethylsilane and formaldehyde followed by methanol and anhydrous potassium carbonate.
  • an exo isomer may be obtained by epimerisation of a corresponding endo isomer and vice versa, the epimerisation reaction being effected by standard procedures at any convenient stage in the process.
  • the different stereoisomeric forms of compounds of formula (I) may be separated one from the other by the usual methods, for example using chromatographic methods. Enantiomers may be separated using chiral resolving agents such as (S)-(+)- and (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, or chiral chromatography, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • chiral resolving agents such as (S)-(+)- and (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, or chiral chromatography, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • compositions of formula (I) may be formed conventionally by reaction with the appropriate acid such as described above under formula (I).
  • the compounds of the present invention enhance acetylcholine function via an action at muscarinic receptors within the central nervous system and are therefore of potential use in the treatment and/or prophylaxis of dementia.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.
  • composition of the invention is in the form of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example star
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
  • the invention also provides a method of treatment and/or prophylaxis of dementia in mammals including humans, which comprises administering to the sufferer an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • suitable unit doses may be 0.05 to 100 mg, for example 0.2 to 50 mg and such unit doses may be administered more than once a day, for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 5 mg/kg and such therapy may extend for a number of weeks or months.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
  • the invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of dementia.
  • n-Butyllithium (7.3 ml of a 1.6M solution in hexane, 0.0117 mole) was added dropwise to (trimethylsilyl)acetylene (1.57 ml, 0.0111 mole) in dry THF (50 ml) at -70° C.
  • the resulting solution was stirred at -70° C. for 0.5 h then added dropwise by cannula to ( ⁇ ) 1-azabicyclo[3.2.1]oct-5-yl-N-methoxy-N-methylcarboxamide (D5, 1.83 g, 0.0092 mole) in dry THF (50 ml) at -70° C.
  • Ethyl 1 -azabicyclo[2.2.1]hept-4-ylcarboxylate hydrobromide salt (D17, 16.85 g, 0.067 mole) was converted to the acid chloride hydrochloride salt and treated with methoxylamine hydrochloride (6.19 g, 0.074 mole) and triethylamine as in the method of Description 8 to give the title compound (D18) as a pale brown crystalline solid (4.60 g, 40%) m.p. 129°-134° C.
  • reaction mixture was cooled on ice, treated with saturated aqueous potassium carbonate (50 ml) and water (50 ml). The aqueous and organic phases were separated, and the aqueous phase extracted with chloroform (3 ⁇ 200 ml). The combined organic extracts were dried (Na 2 SO 4 ) and evaporated to an oil which was chromatographed on silica gel in a gradient of 0-20% methanol in chloroform to afford the title compound (D26) as an oil (0.13 g, 3%).
  • Aqueous 12M sodium hydroxide (15 ml) at 0° C. was added to a mixture of 1-azabicyclo[3.2. ]oct-5-yl trimethylsilylethynyl ketone O-methyloxime (D7, 0.63 g, 0.0024 mole) and triethylbenzylamine bromide (0.22 g, 0.80 mole) in acetonitrile (15 ml) at 0° C.
  • the reaction mixture was stirred at 0° C. for 10 minutes then diluted with ether (100 ml).
  • the organic phase was separated, dried (Na 2 SO 4 ), and evaporated.
  • Oxalate salt 1 H Nmr (major isomer, d 6 DMSO) ⁇ : 1.65-2.25 (6H, m), 3.09-3.57 (6H, m), 3.86 (3H, s), 5.04 (1H, s)
  • Triphenylphosphine (2.20 g, 0.0084 mole) was added in a single portion to 1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide (D8, 1.54 g, 0.0084 mole) and carbon tetrachloride (2 ml) in acetonitrile (50 ml) at reflux. After 2 minutes the reaction mixture was poured into saturated aqueous potassium carbonate solution (30 ml) and extracted with chloroform (4 ⁇ 50 ml).
  • Triphenylphosphine (0.86 g, 0.0033 mole) was added to a mixture of 1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide (D8, 0.6 g, 0.0033 mole) and carbon tetrabromide (1.09 g, 0.0033 mole) in acetonitrile (30 ml) at reflux.
  • the reaction mixture was refluxed for 4 h then poured into saturated potassium carbonate (30 ml) and extracted with chloroform (5 ⁇ 50 ml).
  • Oxalate salt 1 H Nmr (d 6 DMSO) ⁇ : 1.72-2.26 (6H, m), 3.15-3.55 (6H, m), 3.93 (3H, s).
  • exo-1-Azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide (D10, 0.4 g, 0.0024 mole) was treated with triphenylphosphine (0.62 g, 0.0024 mole) and carbon tetrachloride (1 ml) in acetonitrile (30 ml) as in the method of Example 5 to give the imidoyl chloride as a colourless oil (0.15 g, 34%). A portion of this material was converted to the oxalate salt and recrystallised from acetone/methanol to yield the title compound (E8) as a white crystalline solid m.p. 118°-120° C.
  • Oxalate salt 1 H Nmr (d 6 DMSO) ⁇ : 1.68 (1H, m), 1.98 (1H, m), 3.02-3.53 (8H, m), 3.91 (3H, s).
  • the purity of the enantiomer was confmned as >95% by chiral HPLC [2 ⁇ (chiral - AGP, 100 ⁇ 4.0 mm) coupled in series to make a total column length of 200 mm using 0.02M of phosphate (pH 7.0) as eluant].
  • the white crystalline solid was filtered off (416 mg) and recrystallised twice from methanol/acetone to give 297 mg of a white solid.
  • This material was treated with saturated potassium carbonate (50 ml) and extracted with chloroform (3 ⁇ 50 ml). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated in vacuo to give a colourless oil (94 mg), which was converted to the oxalate salt and recrystallised from methanol/acetone to give the title compound (E30) as a white solid m.p. 154°-156° C.
  • Non-specific binding of 3H-QNB is defined using 1 ⁇ M Atropine sulphate (2 ⁇ M Atropine) and of 3H-OXO-M using 10 ⁇ M Oxotremorine.
  • Non-specific binding values typically are 5% and 25% of total binding, respectively.
  • Incubations are carried out at 37° C. for 30 min and the samples filtered using Whatman GF/B filters. (In the 3H-OXO-M experiments the filters are presoaked for 30 min in 0.05% polyethylenimine in water). Filters are washed with 3 ⁇ 4 ml ice-cold buffer. Radioactivity is assessed using a Packard BPLD scintillation counter, 3 ml Pico-Fluor 30 (Packard) as scintillant.
  • This test provides an indication of the muscarinic binding activity of the test compound.
  • the results are obtained as IC 50 values (i.e. the concentration which inhibits binding of the ligand by 50%) for the displacement of the muscarinic agonist 3H-OXO-M and the muscarinic antagonist 3H-QNB.
  • IC 50 values i.e. the concentration which inhibits binding of the ligand by 50%
  • the ratio IC 50 (3H-QNB)/IC 50 (3H-OXO-M) gives an indication of the agonist character of the compound.
  • Agonists typically exhibit a large ratio; antagonists typically exhibit a ratio near to unity.
  • Table 1 The results are shown in Table 1.

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  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US08/585,113 1989-04-13 1996-01-11 Azabicylo oxime compounds Expired - Lifetime USRE35593E (en)

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GB898908365A GB8908365D0 (en) 1989-04-13 1989-04-13 Novel compounds
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GB8923299 1989-10-16
US50810090A 1990-04-11 1990-04-11
US07/785,884 US5278170A (en) 1989-04-13 1991-10-30 Azabicylo oxime compounds
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859024A (en) * 1996-05-13 1999-01-12 Zeneca Limited Insecticidal, acaricidal or nematicidal 3-cyano-8-azabicyclo 3.2.1!octane derivatives
US20070049576A1 (en) * 2005-08-26 2007-03-01 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
US7678808B2 (en) 2006-05-09 2010-03-16 Braincells, Inc. 5 HT receptor mediated neurogenesis
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
EP2258359A2 (de) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenese durch Modulation des Muscarinrezeptors mit Sabcomelin
EP2314289A1 (de) 2005-10-31 2011-04-27 Braincells, Inc. Gaba-rezeptor-vermittelte modulation von neurogenese
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents
US7998971B2 (en) 2006-09-08 2011-08-16 Braincells Inc. Combinations containing a 4-acylaminopyridine derivative
EP2377530A2 (de) 2005-10-21 2011-10-19 Braincells, Inc. Modulation von Neurogenese durch PDE-Hemmung
EP2377531A2 (de) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenese mittels Angiotensin-Modulation

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Publication number Priority date Publication date Assignee Title
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EP0552213A1 (de) * 1990-10-12 1993-07-28 Beecham Group Plc 1,2,5,6-tetrahydropyridinoximderivate
WO1992011261A1 (en) * 1990-12-21 1992-07-09 Merck Sharp & Dohme Limited 4-azatricyclo[2.2.1.02,6]heptanes and pharmaceutical compositions
MX9300875A (es) * 1992-02-20 1993-08-31 Smithkline Beecham Plc Procedimiento para la preparacion de compuestos azabiciclicos.
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GB9421472D0 (en) * 1994-10-25 1994-12-07 Smithkline Beecham Plc Novel methods
AR004178A1 (es) * 1995-07-29 1998-11-04 Smithkline Beecham Plc Procedimiento para la formulacion de un farmaco, una composicion farmaceutica obtenible mediante este procedimiento y el uso de la misma.
AU751607B2 (en) * 1995-07-29 2002-08-22 Smithkline Beecham Plc Method of treatment of dementia
GB9615628D0 (en) * 1996-07-25 1996-09-04 Smithkline Beecham Plc Formulation
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Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0094742A2 (de) * 1982-04-14 1983-11-23 Beecham Group Plc Substituierte Azabicyclo-Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
US4546185A (en) * 1982-08-17 1985-10-08 Pharmuka Laboratoires Process for the preparation of derivatives of quinuclidine substituted in the 3 position
EP0239445A2 (de) * 1986-02-27 1987-09-30 Roussel-Uclaf 1,2,5,6-Tetrahydropyridin-3-carboxaldehydoximderivate, Verfahren zur Herstellung, sie enthaltende Zusammensetzungen und deren Anwendung als Heilmittel
US4710508A (en) * 1986-12-08 1987-12-01 Warner-Lambert Company O-substituted tetrahydropyridine oxime cholinergic agents
EP0257741A2 (de) * 1986-06-27 1988-03-02 Beecham Group Plc Azabicyclische Verbindungen, Verfahren und Zwischenprodukte zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen
EP0261763A1 (de) * 1986-06-27 1988-03-30 Beecham Group Plc Verbrückte bicyclische N-heterocyclische Verbindungen
EP0271798A2 (de) * 1986-12-08 1988-06-22 Warner-Lambert Company Substituierte Tetrahydropyridinoxime und ihre Verwendung als cholinergische Heilmittel
EP0287356A2 (de) * 1987-04-15 1988-10-19 Beecham Group Plc Am Brückenkopf substituierte Azabicyclenderivate
EP0288394A2 (de) * 1987-04-24 1988-10-26 Roussel-Uclaf 1,2,5,6-Tetrahydropyridin-Derivate, Verfahren zur Herstellung, Verwendung als Heilmittel und Zusammenstellungen, die sie enthalten
EP0291673A1 (de) * 1987-03-31 1988-11-23 Warner-Lambert Company Tetrahydropyridin-oxime, Verfahren zu ihrer Herstellung und ihre Verwendung als cholinergische Mittel
EP0308284A1 (de) * 1987-08-21 1989-03-22 Roussel-Uclaf 1,2,5,6-Tetrahydropyridinoxim-Derivate, Verfahren zu deren Herstellung, deren Verwendung als Arzneimittel und diese enthaltende Zusammensetzungen
EP0308283A1 (de) * 1987-08-21 1989-03-22 Roussel-Uclaf 1,2,5,6-Tetrahydropyridin-3-carboxaldehydoxim-Derivate, Verfahren zu deren Herstellung, deren Verwendung als Arzneimittel und diese enthaltende Zusammensetzungen
EP0316713A2 (de) * 1987-11-13 1989-05-24 Kurt Gerhard Fickelscher Planetengetriebe
EP0338723A1 (de) * 1988-04-15 1989-10-25 Beecham Group Plc Chemische Verbindungen
US4927837A (en) * 1987-12-30 1990-05-22 Roussel Uclaf Derivatives of 3-piperidine carbaldehyde oxime and their use as medicaments
US4937239A (en) * 1989-02-13 1990-06-26 Warner-Lambert Company Azabicycloalkane oxime & azabicycloalkene oxime muscarinic agents
US5015655A (en) * 1988-10-28 1991-05-14 Roussel Uclaf 1-azabicycloalkane derivatives, their preparation process and their use as medicaments
US5217975A (en) * 1989-06-06 1993-06-08 Beecham Group P.L.C. Azabicyclic compounds for treating dementia

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL88156A (en) * 1987-11-13 1997-02-18 Novo Nordisk As Azacyclic compounds their preparation and pharmaceutical compositions containing them

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0094742A2 (de) * 1982-04-14 1983-11-23 Beecham Group Plc Substituierte Azabicyclo-Verbindungen, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zusammensetzungen
US4546185A (en) * 1982-08-17 1985-10-08 Pharmuka Laboratoires Process for the preparation of derivatives of quinuclidine substituted in the 3 position
EP0239445A2 (de) * 1986-02-27 1987-09-30 Roussel-Uclaf 1,2,5,6-Tetrahydropyridin-3-carboxaldehydoximderivate, Verfahren zur Herstellung, sie enthaltende Zusammensetzungen und deren Anwendung als Heilmittel
EP0257741A2 (de) * 1986-06-27 1988-03-02 Beecham Group Plc Azabicyclische Verbindungen, Verfahren und Zwischenprodukte zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen
EP0261763A1 (de) * 1986-06-27 1988-03-30 Beecham Group Plc Verbrückte bicyclische N-heterocyclische Verbindungen
US4710508A (en) * 1986-12-08 1987-12-01 Warner-Lambert Company O-substituted tetrahydropyridine oxime cholinergic agents
EP0271798A2 (de) * 1986-12-08 1988-06-22 Warner-Lambert Company Substituierte Tetrahydropyridinoxime und ihre Verwendung als cholinergische Heilmittel
EP0291673A1 (de) * 1987-03-31 1988-11-23 Warner-Lambert Company Tetrahydropyridin-oxime, Verfahren zu ihrer Herstellung und ihre Verwendung als cholinergische Mittel
US5132316A (en) * 1987-04-15 1992-07-21 Beecham Group P.L.C. Heterocyclic azabicyclic compounds for enhancing acetylcholine function
EP0287356A2 (de) * 1987-04-15 1988-10-19 Beecham Group Plc Am Brückenkopf substituierte Azabicyclenderivate
EP0288394A2 (de) * 1987-04-24 1988-10-26 Roussel-Uclaf 1,2,5,6-Tetrahydropyridin-Derivate, Verfahren zur Herstellung, Verwendung als Heilmittel und Zusammenstellungen, die sie enthalten
EP0308284A1 (de) * 1987-08-21 1989-03-22 Roussel-Uclaf 1,2,5,6-Tetrahydropyridinoxim-Derivate, Verfahren zu deren Herstellung, deren Verwendung als Arzneimittel und diese enthaltende Zusammensetzungen
EP0308283A1 (de) * 1987-08-21 1989-03-22 Roussel-Uclaf 1,2,5,6-Tetrahydropyridin-3-carboxaldehydoxim-Derivate, Verfahren zu deren Herstellung, deren Verwendung als Arzneimittel und diese enthaltende Zusammensetzungen
EP0316713A2 (de) * 1987-11-13 1989-05-24 Kurt Gerhard Fickelscher Planetengetriebe
US4927837A (en) * 1987-12-30 1990-05-22 Roussel Uclaf Derivatives of 3-piperidine carbaldehyde oxime and their use as medicaments
EP0338723A1 (de) * 1988-04-15 1989-10-25 Beecham Group Plc Chemische Verbindungen
US5110828A (en) * 1988-04-15 1992-05-05 Beecham Group P.L.C. Azabicyclo oxime derivatives
US5015655A (en) * 1988-10-28 1991-05-14 Roussel Uclaf 1-azabicycloalkane derivatives, their preparation process and their use as medicaments
US4937239A (en) * 1989-02-13 1990-06-26 Warner-Lambert Company Azabicycloalkane oxime & azabicycloalkene oxime muscarinic agents
US5217975A (en) * 1989-06-06 1993-06-08 Beecham Group P.L.C. Azabicyclic compounds for treating dementia

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5859024A (en) * 1996-05-13 1999-01-12 Zeneca Limited Insecticidal, acaricidal or nematicidal 3-cyano-8-azabicyclo 3.2.1!octane derivatives
EP2258358A2 (de) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenese mit Acetylcholinesterasehemmer
EP2275096A2 (de) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese durch modulation des Muscarinrezeptors
US7678363B2 (en) 2005-08-26 2010-03-16 Braincells Inc Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs
US20100120842A1 (en) * 2005-08-26 2010-05-13 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
EP2275095A2 (de) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenese durch modulation des Muscarinrezeptors
EP2258359A2 (de) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenese durch Modulation des Muscarinrezeptors mit Sabcomelin
EP2258357A2 (de) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenese mit Acetylcholinesterasehemmer
US20070049576A1 (en) * 2005-08-26 2007-03-01 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
EP2377530A2 (de) 2005-10-21 2011-10-19 Braincells, Inc. Modulation von Neurogenese durch PDE-Hemmung
EP2314289A1 (de) 2005-10-31 2011-04-27 Braincells, Inc. Gaba-rezeptor-vermittelte modulation von neurogenese
US7678808B2 (en) 2006-05-09 2010-03-16 Braincells, Inc. 5 HT receptor mediated neurogenesis
EP2377531A2 (de) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenese mittels Angiotensin-Modulation
EP2382975A2 (de) 2006-05-09 2011-11-02 Braincells, Inc. Neurogenese mittels Angiotensin-Modulation
US7998971B2 (en) 2006-09-08 2011-08-16 Braincells Inc. Combinations containing a 4-acylaminopyridine derivative
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents

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SG48315A1 (en) 1998-04-17
JPH09188678A (ja) 1997-07-22
JPH09188679A (ja) 1997-07-22
CA2014379A1 (en) 1990-10-13
JPH037285A (ja) 1991-01-14
EP0392803A1 (de) 1990-10-17
ES2219636T3 (es) 2004-12-01
DE69034146D1 (de) 2004-07-22
KR0185378B1 (ko) 1999-05-01
PT93753A (pt) 1990-11-20
HK1012365A1 (en) 1999-07-30
KR900016211A (ko) 1990-11-12
JP2913466B2 (ja) 1999-06-28
DE69034146T2 (de) 2005-07-14
JP2665818B2 (ja) 1997-10-22
ATE269330T1 (de) 2004-07-15
JP2913467B2 (ja) 1999-06-28
PT93753B (pt) 1996-08-30
AU619969B2 (en) 1992-02-06
EP0392803B1 (de) 2004-06-16
DK0392803T3 (da) 2004-10-18
AU5315990A (en) 1990-10-18
NZ233290A (en) 1992-06-25
CA2014379C (en) 2000-02-08

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